Clinical Trials /

Nivolumab and Relatlimab in Treating Participants With Advanced Chordoma

NCT03623854

Description:

This phase II trial studies how well nivolumab and relatlimab work in treating participants with chordoma that has spread to other places in the body. Monoclonal antibodies, such as nivolumab and relatlimab, may interfere with the ability of tumor cells to grow and spread.

Related Conditions:
  • Chordoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab and Relatlimab in Treating Participants With Advanced Chordoma
  • Official Title: A Signal Finding Phase 2 Study of Nivolumab (Anti-PD-1; BMS-936558; ONO-4538) and Relatlimab (Anti-LAG-3 Monoclonal Antibody; BMS-986016) in Patients With Advanced Chordoma

Clinical Trial IDs

  • ORG STUDY ID: 18-000597
  • SECONDARY ID: NCI-2018-01517
  • SECONDARY ID: 18-000597
  • SECONDARY ID: P30CA016042
  • NCT ID: NCT03623854

Conditions

  • Chordoma
  • Locally Advanced Chordoma
  • Metastatic Chordoma
  • Unresectable Chordoma

Interventions

DrugSynonymsArms
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoTreatment (nivolumab and relatlimab)
RelatlimabBMS-986016, BMS986016, Immunoglobulin G4, Anti-(human Lymphocyte Activation Gene-3 Protein) (Human Heavy Chain), Disulfide with Human Light Chain, DimerTreatment (nivolumab and relatlimab)

Purpose

This phase II trial studies how well nivolumab and relatlimab work in treating participants with chordoma that has spread to other places in the body. Monoclonal antibodies, such as nivolumab and relatlimab, may interfere with the ability of tumor cells to grow and spread.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To assess the clinical benefit of the combination of nivolumab and relatlimab in patients
      with advanced chordomas by objective response rate (ORR).

      SECONDARY OBJECTIVES:

      I. Ascertain the safety of nivolumab in combination with relatlimab in subjects with
      metastatic or locally advanced/unresectable chordoma by the frequency of adverse events
      (AEs).

      II. Assess the clinical benefit of the combination of nivolumab and relatlimab in patients
      with advanced chordomas by progression free survival (PFS).

      EXPLORATORY OBJECTIVES:

      I. Compare response rate (RR) and clinical benefit rate (CBR) in patients whose tumors are
      PD-L1+ and PD-L1- at baseline.

      II. Compare RR and CBR in patients whose tumors are LAG-3+ and LAG-3- at baseline.

      III. In the patients who are PD-L1 positive, compare RR and CBR in patients with 1% and 5%
      tumor membrane staining.

      III. Determine the response to treatment based on the baseline mutation load. IV. Determine
      the ORR and CBR via Choi criteria.

      OUTLINE:

      Participants receive nivolumab intravenously (IV) over 60 minutes and relatlimab via infusion
      over 60 minutes on day 1. Courses repeat every 28 days for up to 2 years in the absence of
      disease progression or unacceptable toxicity.

      After completion of study treatment, participants are followed up within 100 days.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (nivolumab and relatlimab)ExperimentalParticipants receive nivolumab intravenously (IV) over 60 minutes and relatlimab via infusion over 60 minutes on day 1. Courses repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
  • Nivolumab
  • Relatlimab

Eligibility Criteria

        Inclusion Criteria:

          -  Written informed consent must be obtained from the subject/legal representative prior
             to performing any protocol-related procedures, including screening evaluations.

          -  Capable of providing informed consent and complying with trial procedures.

          -  Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1.

          -  Life expectancy > 12 weeks.

          -  Histological confirmation of chordoma.

          -  Adequate archival tissue must be available within 6 months prior to signing consent.
             If not, an adequate tumor specimen obtained by either excisional biopsy, incisional
             biopsy or core needle biopsy must be sent to the central pathology lab for evaluation.
             The material must measure at least 0.8 x 0.1 cm in size or contain at least 50 tumor
             cells.

          -  Locally advanced, unresectable, and/or metastatic chordoma with evidence of disease
             progression by either computed tomography (CT) or magnetic resonance imaging (MRI)
             scan, or loss of neurologic function on or after the last cancer therapy within 6
             months prior to randomization.

          -  Measurable tumor lesions according to Response Evaluation Criteria in Solid Tumors
             (RECIST) 1.1 criteria.

          -  Women must not be able to become pregnant (e.g., post-menopausal for at least 1 year,
             surgically sterile, or practicing adequate birth control methods) for the duration of
             the study. (Adequate contraception includes: oral contraception, implanted
             contraception, intrauterine device implanted for at least 3 months, or barrier method
             in conjunction with spermicide.)

          -  Women must not be breastfeeding.

          -  Males and their female partner(s) of child-bearing potential must use 2 forms of
             effective contraception (condom or vasectomy for males) from the last menstrual period
             of the female partner during the study treatment and agree to continue use for 6
             months after the final dose of study treatment.

          -  Reproductive status:

               -  Women of childbearing potential (WOCBP) must have a negative serum or urine
                  pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human
                  chorionic gonadotropin [HCG]) at screening.

               -  Women must not be breastfeeding.

               -  Women of childbearing potential (WOCBP) must agree to follow instructions for
                  method(s) of contraception for the duration of treatment with study treatments
                  plus 24 weeks after the last dose of study treatment.

               -  Males who are sexually active with WOCBP must agree to follow instructions for
                  method(s) of contraception for the duration of treatment with study treatments
                  plus 33 weeks after the last dose of study treatment. Male participants must be
                  willing to refrain from sperm donation during this time.

               -  Azoospermic males are exempt from contraceptive requirements. WOCBP who are
                  continuously not heterosexually active are also exempt from contraceptive
                  requirements, and still must undergo pregnancy testing as described in this
                  section.

               -  Male subjects must be willing to refrain from sperm donation during the entire
                  study and for 5 half-lives of study drug plus 90 days (duration of sperm
                  turnover) XX days after dosing has been completed.

               -  Investigators shall counsel WOCBP, and male subjects who are sexually active with
                  WOCBP, on the importance of pregnancy prevention and the implications of an
                  unexpected pregnancy. Investigators shall advise on the use of highly effective
                  methods of contraception, which have a failure rate of < 1% when used
                  consistently and correctly.

          -  Hemoglobin >= 8 g/dL.

          -  Absolute neutrophil count >= 1,500/mm^3.

          -  Platelet count >= 75,000/mm^3.

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 ?
             institutional upper limit of normal (ULN); for subjects with liver metastases, AST or
             ALT =< 5 ? ULN.

          -  Bilirubin =< 1.5 x ULN; for subjects with documented/suspected Gilbert?s disease,
             bilirubin =< 3 x ULN.

          -  Left ventricular ejection fraction (LVEF) assessment with documented LVEF >= 50% by
             either transthoracic echocardiography (TTE) or multiple-gated acquisition (MUGA) (TTE
             preferred test) within 6 months from first study drug administration.

          -  Willingness to provide consent for biopsy samples. Tumor biopsies will be required for
             all subjects. Tumor lesions used for biopsy should not be lesions used as RECIST
             target lesions, unless there are no other lesions suitable for biopsy. If a RECIST
             target lesion is used for biopsy the lesion must be >= 2 cm in longest diameter.

        Exclusion Criteria:

          -  Palliative surgery and/or radiation treatment within 28 days prior to date of
             randomization; also no steroids are permitted as of 28 days of starting the study.

          -  Inability to give informed consent.

          -  Exposure to any therapeutic agent (investigational or conventional) within 7 days of
             date of randomization or to any agent for which 5 half lives have not elapsed.

          -  An inadequate tumor specimen as defined by the central pathologist.

          -  History of other malignancies except cured basal cell carcinoma, cutaneous squamous
             cell carcinoma, melanoma in situ, superficial bladder cancer or carcinoma in situ of
             the cervix; for other malignancies, must be documented to be free of cancer for >= 2
             years. All other cases can be considered on a case by case basis at the discretion of
             the principal investigator.

          -  Current, serious, clinically significant cardiac arrhythmias or hypertension that is
             not adequately controlled, per investigator discretion.

          -  Concomitant use of medications associated with a high incidence of QT prolongation
             will require clearance by medical monitor.

          -  Active, clinically significant serious infection requiring treatment with antibiotics,
             anti-virals or anti-fungals. The Medical Monitor should be contacted for any
             uncertainties.

          -  Any condition that might interfere with the subject?s participation in the study,
             safety, or in the evaluation of the study results.

          -  Concurrent enrollment in another clinical study, unless it is an observational
             (non-interventional) clinical study or the follow-up period of an interventional
             study.

          -  Prior exposure to any anti-LAG3 antibodies. (prior PD-1/PD-L1 antibodies are
             permitted).

          -  Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer
             treatment. Concurrent use of hormones for non-cancer-related conditions (eg, insulin
             for diabetes and hormone replacement therapy) is acceptable.

          -  Current or prior use of immunosuppressive medication within 28 days before the first
             dose of nivolumab, with the exceptions of intranasal, topical, and inhaled
             corticosteroids or systemic corticosteroids at physiologic doses not to exceed 10
             mg/day of prednisone or equivalent (use for brain metastases is not permitted 28 days
             prior to start of therapy).

          -  Active or prior documented autoimmune disease within the past 3 years.

               -  Note: Subjects with active, known or suspected autoimmune disease such as
                  vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune
                  condition only requiring hormone replacement, psoriasis not requiring systemic
                  treatment, or conditions not expected to recur in the absence of an external
                  trigger are permitted to enroll.

          -  History of organ transplant that requires use of immunosuppressives.

          -  Active or prior documented inflammatory bowel disease (e.g. Crohn?s disease,
             ulcerative colitis) or a history of primary immunodeficiency.

          -  Known history of tuberculosis.

          -  Unresolved toxicities from prior anticancer therapy, defined as having not resolved to
             National Cancer Institute?s (NCI?s) Common Terminology Criteria for Adverse Events
             (CTCAE) (NCI CTCAE version [v]4.03) grade 0 or 1, or to levels dictated in the
             inclusion/exclusion criteria with the exception of alopecia. Subjects with
             irreversible toxicity that is not reasonably expected to be exacerbated by nivolumab
             may be included (eg, hearing loss) after consultation with the Bristol-Myers Squibb
             (BMS) medical monitor.

          -  Subjects who active hepatitis B or C, or human immunodeficiency virus (HIV).

          -  Receipt of live attenuated vaccination within 30 days of receiving nivolumab or
             anti-LAG3 antibody.

          -  Prisoners or subjects who are involuntarily incarcerated.

          -  Subjects who are compulsorily detained for treatment of either a psychiatric or
             physical (e.g, infectious disease) illness.

          -  Uncontrolled or significant cardiovascular disease including, but not limited to, any
             of the following:

               -  Myocardial infarction (MI) or stroke/transient ischemic attack (TIA) within the 6
                  months prior to consent.

               -  Uncontrolled angina within the 3 months prior to consent.

               -  Any history of clinically significant arrhythmias (such as ventricular
                  tachycardia, ventricular fibrillation, or torsades de pointes, or poorly
                  controlled atrial fibrillation).

               -  Corrected QT (QTc) prolongation > 480 msec.

               -  History of other clinically significant cardiovascular disease (i.e.,
                  cardiomyopathy, congestive heart failure with New York Heart Association [NYHA]
                  functional classification III-IV, pericarditis, significant pericardial effusion,
                  significant coronary stent occlusion, poorly controlled venous thrombus).

               -  Cardiovascular disease-related requirement for daily supplemental oxygen.

               -  History of two or more MIs or two or more coronary revascularization procedures.

               -  Subjects with history of myocarditis, regardless of etiology.

               -  Subjects with history of life-threatening toxicity related to prior immune
                  therapy (eg. anti-cytotoxic T-lymphocyte-associated protein [CTLA]-4 or
                  anti-PD-1/PD-L1 treatment or any other antibody or drug specifically targeting
                  T-cell co-stimulation or immune checkpoint pathways) except those that are
                  unlikely to re-occur with standard countermeasures (eg, hormone replacement after
                  endocrinopathy).

               -  Troponin T (TnT) or I (TnI) > 2 x institutional ULN. Subjects with TnT or TnI
                  levels between > 1 to 2 x ULN will be permitted if repeat levels within 24 hours
                  are 1 x ULN. If TnT or TnI levels are > 1 to 2 x ULN within 24 hours, the subject
                  may undergo a cardiac evaluation and be considered for treatment, following a
                  discussion with the BMS medical monitor or designee. When repeat levels within 24
                  hours are not available, a repeat test should be conducted as soon as possible.
                  If TnT or TnI repeat levels beyond 24 hours are < 2 x ULN, the subject may
                  undergo a cardiac evaluation and be considered for treatment, following a
                  discussion with the BMS Medical Monitor or designee.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:12 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (ORR) defined as the number of subjects with a best objective response (BOR) of confirmed complete response (CR) or partial response (PR) divided by the number of subjects
Time Frame:Up to 2 years
Safety Issue:
Description:BOR is defined as the best response designation, as determined by the principal investigator, recorded between the date of randomization and the date of objectively documented progression per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or the date of subsequent therapy (including tumor-directed radiotherapy and tumor-directed surgery), whichever occurs first.

Secondary Outcome Measures

Measure:Response rate by Choi criteria
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Progress free survival (PFS) time
Time Frame:At 4 months and 6 months
Safety Issue:
Description:
Measure:Clinical benefit rate as defined by adding CR, PR, and stable disease (SD)
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Incidence of adverse events according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Time Frame:Up to 2 years
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Jonsson Comprehensive Cancer Center

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